Activation, Phenotype and Function of CD4 T Cells in Schistosoma-Pulmonary Hypertension

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Summary/Abstract Inflammation has important roles in the pathogenesis of pulmonary arterial hypertension (PAH), but whether inflammation is causal, an amplifier of alternative triggering mechanisms, or an epiphenomenon remains unclear. Prior studies in this area have largely focused on innate immunity, sterile models, and single cytokines or cells in the absence of a well-defined pathobiological context—approaches that cannot address aspects of adaptive immunity or innate-adaptive immunity crosstalk which contribute to vascular disease. To address these limitations, our group studies the parasite Schistosoma, the cause of schistosomiasis which may be the most prevalent form of PAH worldwide. Using a Schistosoma-pulmonary hypertension (PH) murine model, studies in the prior period identified a series of mechanistic events which are critical for PH development: Th2-activation of CD4 T cells in the lungs; which recruit of CCR2+ Ly6c+ monocytes to the adventitial space that express thrombospondin-1 (TSP-1); and the TSP-1 functionally activates latent TGF-β, causing vascular remodeling. This proposal builds on this foundation by now interrogating adaptive and innate immune interfaces that we believe to be necessary to Schistosoma-PH pathogenesis. We extend our studies to translational analysis of human biospecimens, seeking proteins that correlate with PAH presence in an at-risk group with severe schistosomiasis. This proposal will test the hypothesis that intrapulmonary dendritic cells (DCs) present Schistosoma antigen to CD4 T cells which support Th2 polarization, causing activation of interstitial macrophages (IMs), who release the CCR2 ligands CCLs 2, 7 and 12, driving TSP-1+ monocyte recruitment, TGF-β activation, and PH. We also hypothesize that key proteins that increase risk of PAH—including CCL2, CCL7, CCL12, and TSP-1—can be detected in human plasma. We propose 4 Aims. Aim 1 will determine that antigen presentation by a specific DC subset, cDC2s, is required for T cell activation in Schistosoma-PH. Aim 2 will determine if the balance of Th1 to Th2 inflammation drives monocyte/macrophage and PH phenotypes in Schistosoma-PH. Aim 3 will determine that CCL2/7/12 release by IMs is required for TSP1+ monocyte recruitment in Schistosoma-PH. Aim 4 will identify plasma proteins associated with PAH development in subjects with schistosomiasis. This translational Aim will be achieved by developing and characterizing two cohorts of subjects recruited from 4 clinical centers in Brazil: subjects with the precursor condition schistosomiasis hepatosplenic disease (SchHSD) who are unlikely to have PAH on the basis of echocardiography screening, and subjects with SchHSD who have right heart catheterization-confirmed PAH. Completion of these studies will lead to understanding the role of innate and adaptive immunity in the development of Schistosoma-PAH, and create opportunities for entirely novel approaches to diagnosing and potentially treating this disease. We propose to identify mechanistic proteins which correlate with disease presence in blood, facilitating screening of at-risk subjects in low-resource areas.